Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used and therapeutically effective groups of drugs. However, gastric irritation problems constitute the most frequently recognized adverse side effect following oral administration of NSAIDs. Such side effects are well recognized and must be weighed against the clinical efficacy of the drugs.
A great amount of research has been undertaken in an attempt to understand the underlying mechanism responsible for these effects. For example, Cioli et al, Tox. and Appl. Pharm., 50, 283-289 (1979) suggest that gastrointestinal lesions in laboratory animals resulting from the oral administration of acidic NSAIDs may depend on two different mechanisms: a local action exerted by contact with the gastric mucosa and a generalized/centrally mediated (systemic) action, taking place following oral administration.
More recently, Price et al, Drugs 40 (Suppl. 5):1-11, 1990, suggest that NSAID-induced gastric damage occurs as a result of NSAID-mediated direct and indirect acidic damage followed almost simultaneously by the deleterious systemic effect of prostaglandin inhibition.
A variety of strategies have been used in the management of NSAID-induced gastric damage. These include: 1) the development and use of NSAIDs with less toxic potential; 2) the reduction or elimination of the agent that actually causes the injury; and 3) the enhancement of the mucosal defense. However, these approaches have not proven entirely successful.
For example, the most effective means of preventing gastric damage, i.e., by eliminating the primary aetiological agent is rarely feasible with NSAIDs inasmuch as patients with severe inflammatory disease are rarely able to cease using these drugs. Although selection of less toxic NSAIDs should prove useful, the only practical solution, at present, is to treat the NSAID induced gastric damage. Misoprostol (a methylated prostaglandin E.sub.1) has been approved by the FDS for use in preventing NSAID gastropathy. However, Misoprostol is expensive, must be administered multiple times daily and can cause unacceptable side effects.
In copending U.S. application Ser. No. 07/897,193 filed Jun. 10, 1992,Now Abandoned the use of NSAID particles having a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an average particle size of less than about 400 nm was described as being useful in reducing gastric irritation in mammals.
It would be highly desirable to provide NSAID formulations that can exhibit an even greater reduction in gastric irritation and exhibiting greater enhanced onset of action as an analgesic.